Activin A activation of Smad3 mitigates innate inflammation in mouse models of psoriasis and sepsis.

Summary

The study identifies an activin A–driven, TGF-β–independent activation of Smad3 in macrophages as a natural brake on innate inflammation. By promoting mitochondrial ATP production and adenosine generation via CD73, this axis limits inflammatory outputs; macrophage-specific loss of activin A signaling worsened survival in murine sepsis.

Key Findings

• Bacterial/viral ligands induce activin A via STAT5, which activates Smad3 (pSmad3C) in macrophages independently of TGF-β.
• Activin A–Smad3 signaling enhances mitochondrial ATP production and adenosine generation (via CD73), enforcing anti-inflammatory outputs.
• Macrophage-specific Acvr1b deletion increased mortality in murine sepsis due to uncontrolled inflammation.

Clinical Implications

Therapeutically enhancing activin A–Smad3 signaling (e.g., selective receptor agonism or Smad3 activation) may attenuate hyperinflammation in sepsis while preserving host defense. Patient selection and timing will be critical to avoid immunosuppression.

Limitations

• Findings are based on murine models and ex vivo human macrophages; clinical validation is lacking.
• Potential off-target or fibrosis-related effects of activin/TGF-β superfamily modulation require careful safety evaluation.

Future Directions

Test selective activin receptor agonists or Smad3 activators in clinically relevant sepsis models; define biomarkers for patient stratification and optimal timing; assess safety and dosing windows.